Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Joseph T. Glessner, Kai Wang, Guiqing Cai, Olena Korvatska, Cecilia E. Kim, Shawn Wood, Haitao Zhang, Annette Estes, Camille W. Brune, Jonathan P. Bradfield, Marcin Imielinski, Edward C. Frackelton, Jennifer Reichert, Emily L. Crawford, Jeffrey Munson, Patrick M.A. Sleiman, Rosetta Chiavacci, Kiran Annaiah, Kelly Thomas, Cuiping HouWendy Glaberson, James Flory, Frederick Otieno, Maria Garris, Latha Soorya, Lambertus Klei, Joseph Piven, Kacie J. Meyer, Evdokia Anagnostou, Takeshi Sakurai, Rachel M. Game, Danielle S. Rudd, Danielle Zurawiecki, Christopher J. McDougle, Lea K. Davis, Judith Miller, David J. Posey, Shana Michaels, Alexander Kolevzon, Jeremy M. Silverman, Raphael Bernier, Susan E. Levy, Robert T. Schultz, Geraldine Dawson, Thomas Owley, William M. McMahon, Thomas H. Wassink, John A. Sweeney, John I. Nurnberger, Hilary Coon, James S. Sutcliffe, Nancy J. Minshew, Struan F.A. Grant, Maja Bucan, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Gerard D. Schellenberg, Hakon Hakonarson

Research output: Contribution to journalArticlepeer-review

1087 Scopus citations


Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Original languageEnglish
Pages (from-to)569-572
Number of pages4
Issue number7246
StatePublished - 28 May 2009


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